The long term goal of this Interactive ROl program is to improve the long term survival of patients with colorectal cancer metastatic to the liver. The specific aims of this portion of the IRPG are to understand mechanisms of resistance to fluoropyrimidines in human colon cancer, to develop new therapies based on this experimental data and to provide pharmacologic monitoring for new treatment regimens that are tested in the clinic (Kemeny R0l). The approach will be to use human colon carcinoma cell lines and fresh tumor samples from patients on study to determine mechanisms of natural and acquired resistance to fluoropyrimidines. Samples of colon cancer will be obtained at pump placement (Cohen R0l and Kemeny ROI) from either untreated patients or patients resistant to systemic FUra regimens and mechanisms of fluoropyrimidine resistance studied. In addition, we will also obtain tumor samples from patients at relapse following HAI FUDR for studies of acquired resistance to this drug. Drugs selected that are in various stages of development for HAI are fluoruridine, teroxirone and D1694, a thymidylate synthase inhibitor. Phase I trials are planned for fluoruridine and teroxirone (Kemeny, R0l), as well as hepatic extraction studies, with pharmacologic monitoring.